What is the recommended diagnostic work‑up for suspected autoimmune encephalitis presenting with subacute memory impairment, psychiatric changes, seizures, or movement disorder?

Diagnostic Work-Up for Suspected Autoimmune Encephalitis

For suspected autoimmune encephalitis presenting with subacute memory impairment, psychiatric changes, seizures, or movement disorder, immediately obtain brain MRI with and without contrast, followed by lumbar puncture with CSF testing for neuronal autoantibodies, inflammatory markers (oligoclonal bands, IgG index, IgG synthesis rate), and infectious etiologies, plus serum neuronal autoantibodies—then proceed with EEG and cancer screening based on initial findings. 1

Step 1: Confirm Focal or Multifocal Brain Pathology

Brain MRI with and without contrast is the first-line imaging study 1. Look specifically for:

• T2/FLAIR hyperintensities in medial temporal lobes (limbic encephalitis)
• Cortical-subcortical abnormalities
• Striatal, diencephalic, or brainstem involvement
• Radial perivascular enhancement patterns (suggests GFAP astrocytopathy)

EEG should be obtained if:

• MRI is negative but clinical suspicion remains high
• Patient is encephalopathic
• Frequent seizures are present 1

EEG findings supportive of autoimmune encephalitis include focal slowing/seizures, lateralized periodic discharges, or extreme delta brush (NMDAR-antibody encephalitis). Importantly, a normal EEG does not exclude autoimmune encephalitis but can help differentiate from primary psychiatric disorders 1.

Brain FDG-PET should be considered when:

• MRI is negative AND
• Clinical suspicion remains high after initial testing
• MRI is contraindicated 1

Brain FDG-PET has demonstrated higher sensitivity than MRI in case series and can confirm focal or multifocal brain abnormality when other studies are uninformative 1.

Step 2: Confirm Inflammatory Etiology and Exclude Competing Diagnoses

Lumbar puncture is mandatory and should test for 1:

CSF inflammatory markers:

• Oligoclonal bands
• IgG index
• IgG synthesis rate
• Cell count and differential (pleocytosis supports diagnosis but absence doesn't exclude it)

CSF neuronal autoantibodies (comprehensive panel including):

• NMDAR, LGI1, CASPR2, AMPAR, GABAR antibodies
• GAD65 (high titers clinically relevant)
• GFAP (with typical radial enhancement pattern)
• Paraneoplastic antibodies if indicated 1

CSF infectious workup:

• Bacterial culture and gram stain
• HSV, VZV, HHV6 PCR (critical differential for limbic encephalitis)
• Consider fungal studies, tuberculosis testing based on risk factors
• Cytology if lymphoma or carcinomatosis suspected 1

Serum testing must include:

• Neuronal autoantibodies (same panel as CSF—serum may be positive when CSF is negative)
• Thyroid function and anti-thyroid antibodies
• Additional tests guided by MRI findings and anatomical syndrome (ANA, ANCA, ACE, vitamin B12, RPR based on differential) 1

Critical Pitfall

Do not wait for antibody results to initiate treatment. Approximately 33% of clinically diagnosed autoimmune encephalitis cases may not meet strict 2016 criteria, and seronegative cases can be immunotherapy-responsive 2. The 2021 guidelines emphasize that once infection is ruled out based on basic CSF results (cell count), start immunotherapy empirically 1.

Step 3: Cancer Screening

Initial screening with CT chest, abdomen, and pelvis with contrast in all cases except when contraindicated 1.

If initial CT is negative, add:

• Mammogram/breast MRI (women)
• Pelvic ultrasound (women, especially if NMDAR-antibody suspected)
• Testicular ultrasound (men)
• Whole body FDG-PET if above studies negative 1

Targeted approach: If clinical picture strongly suggests specific antibody (e.g., young woman with psychiatric symptoms and seizures suggesting NMDAR), consider starting with pelvic ultrasound 1.

Diagnostic Algorithm Summary

The 2021 Journal of Neurology, Neurosurgery and Psychiatry guidelines provide the most comprehensive and recent framework [1-1. The diagnostic sequence should proceed systematically:

1. Clinical assessment of subacute onset (<6 weeks) with memory deficits, altered mental status, psychiatric symptoms, seizures, or movement disorders
2. Brain MRI (or FDG-PET if MRI negative/contraindicated)
3. Lumbar puncture with comprehensive CSF analysis
4. Serum autoantibodies and alternative diagnosis exclusion
5. Cancer screening appropriate to presentation
6. Brain biopsy only if diagnosis remains uncertain after above workup 1

Important Nuances

Seronegative cases: Evidence from 2024-2026 case reports demonstrates that seronegative autoimmune encephalitis can respond dramatically to immunotherapy [3-4. When antibodies are negative but clinical picture is compelling (subacute onset, supportive MRI/EEG/CSF findings, exclusion of alternatives), proceed with empiric immunotherapy.

Atypical presentations: Some patients present with isolated seizures, brainstem syndromes without supratentorial findings, or insidious onset—these may not meet strict 2016 criteria but can still represent autoimmune encephalitis, particularly if other autoimmune markers are present 2.

The most common definite autoimmune encephalitis antibodies in clinical practice are LGI1 (34%), NMDAR (16%), and high-titer GAD65 (12%) 2, which should guide your clinical suspicion based on presentation patterns.